<p>With the advent of deep space exploration and ambitious plans to return humans to the Moon and journey onward to Mars, humans will face exposure to ionizing radiation beyond Earth’s atmosphere and magnetosphere. This is particularly concerning for the hematopoietic system that is sensitive to galactic cosmic rays (GCRs) during interplanetary missions. Epidemiological studies and animal studies implicate that exposure to ionizing radiation can cause leukemias, with recent consensus showing that almost all types of leukemias, even chronic lymphocytic leukemia, can be caused by ionizing radiation despite previous controversies. The possible deleterious effects of deep space travel on the formation, development, etiology, and pathophysiology of hematologic malignancies, specifically leukemias, remain largely unclear. The mechanism(s) by which ionizing radiations cause leukemia differs for different leukemia types and is poorly understood in the spaceflight environment, posing a serious health risk for future astronauts. This paper provides a comprehensive review of the various studies and evidence available on Earth and in space assessing the relationship between ionizing radiation and increased risk of leukemia. We also discuss the unique characteristics of leukemia in space, ethical considerations, risk assessments and potential challenges this may bring to astronauts and healthcare professionals as humanity continues to explore the cosmos.</p>